P1102: IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: UPDATED OUTCOMES FROM A MULTICENTRE, REAL-WORLD UK STUDY
Authors: Rohan Shotton, Ann Tivey, Toby A. Eyre, David Lewis, Rebecca Allchin, Harriet Walter, Fiona Miall, Rui Zhao, Anna Santarsieri, Rory Mcculloch, Mark Bishton, Victoria Willimott, Nicole Fowler, Claudia Bedford, Jack Goddard, Samuel Protheroe, Mahesh Prahladan, Miriam Reeve, Shankara Paneesha, Helen Marr, Jamie Wilson, Kushani Ediriwickrema, Chloe Knott, David Wrench, Georgina Talbot, Kim Linton
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Ibrutinib (IBR) is an oral covalent Bruton’s kinase inhibitor licensed for treatment of patients (pts) with relapsed/refractory mantle cell lymphoma (MCL). During the Covid-19 pandemic, IBR +/- rituximab (R) was approved by NHS England for 1st line treatment of MCL as a potentially safer alternative to immunochemotherapy. Limited data are available on the outcomes of ibrutinib-treated pts in the 1st-line setting. Aims: We previously reported outcomes for 66 pts treated under this scheme (EHA 2022, P1141). Here we report data for a larger cohort (n=149) with longer follow-up. Methods: Adults commencing IBR +/- R for untreated MCL under interim Covid-19 arrangements were identified from 43 participating NHS centres in England; data were extracted from hospital records. High-risk disease features were defined as ≥1 of TP53 mutation/deletion, blastoid/pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%. Overall and complete radiological response rates (ORR/CR) were assessed per local investigator according to the Lugano classification using CT and/or PET-CT. Survival analysis was performed using the Kaplan Meier method. Results: 149 pts were enrolled; 74.1% male, median age 75 years (41-94; 10.9% <65), 65.7% stage 4, 34.9% high-risk. 7.8% were considered fit for autologous stem cell transplant (ASCT). Simplified MCL International Prognostic Index (sMIPI) was 0-3 in 13.3%, 4-5 in 36.3% and ≥6 in 50.4%. At median follow-up 15.6 months (m), pts received median 8 (1-33) 28-day IBR cycles. IBR was given with R in 55/141 (39.0%) pts. Starting dose was 560mg in 92.0%. Dose reductions/delays were noted in 33.8%. Of 104 pts who underwent assessment of best response, ORR and CR was 71.2% and 20.2% respectively at a median of 4.9m. For pts with/without high-risk features, ORR was 60.5% vs 77.3% (p=0.069) and CR was 21.1% vs 19.7%. For pts with sMIPI ≥6 vs 0-5, ORR was 66.7% vs 75.0% and CR was 23.5% vs 17.3%. For IBR given with/without R, ORR was 78.7% vs 64.9% and CR was 27.7% vs 14.0% (p=0.085). Median PFS for the whole cohort was 26.0m (18.8-33.2). Median OS was not reached (NR). Median PFS and OS were significantly lower in pts with high-risk features; PFS 9.7m (2.2 – 17.2) vs not reached (NR), p=0.002; OS 14.4m (10.2-18.6) vs NR, p=0.001 (Fig 1). Grade ≥3 any-cause toxicity was reported in 27/133 pts (20.3%), including infection in 7.4%, myelosuppression and bleeding in 4.0% each, and 2 cases of stroke. New onset atrial fibrillation (AF) occurred in 9/126 pts (6.6%; median age 80 (58-94), of which 6 had a history of hypertension or coronary artery stenosis. 62/149 pts (41.6%) discontinued IBR due to progressive disease (PD) (53.2%), toxicity (19.4%), death (12.9%), patient choice (1.6%) and other/unknown reasons (12.9%). 44/149 pts (29.5%) died, due to MCL (n=31, 70.5%), infection (n=6, 13.6%), cardio/cerebrovascular disease (n=5, 11.4%), suicide and unknown cause (both n=1, 2.3%). 26 pts (19.7%) received second-line therapy; ORR and CR were 41.2% and 35.3% respectively. No pts underwent ASCT. Summary/Conclusion: In this real-world study of mostly transplant ineligible MCL pts, first line IBR +/- R was well tolerated and effective, especially in pts with low risk disease. ORR/CR were lower than reported in recent phase II studies (Gine et al 2022, Jain et al 2022), mainly due to inferior outcomes in pts with high-risk disease and impaired performance status, low use of R during the Covid-19 pandemic, and common use of CT for response assessment. Inferior outcomes noted in high-risk pts suggests that novel approaches should be considered in those with aggressive MCL biology.Keywords: ibrutinib, Rituximab, Mantle cell lymphoma